1. Field of the Invention
Camptothecin ("CPT") is a potent inhibitor of the enzyme Topoisomerase I and has demonstrated broad anticancer activity in a variety of preclinical tumor models. The lactone form of CPT is poorly soluble in water and has significant antitumor activity and hydrolysis of E-ring actone to the carboxylate form of CPT greatly increases the water solubility of molecule at the expense of significantly reducing its antitumor activity. A lactone stable form of CPT has not been administered by parenteral or oral routes in human subjects for the purpose of inhibiting the growth of cancer cells. This invention overcomes these limitations and claims novel pharmaceutically acceptable formulations of lactone stable CPT, methods of administration of lactone stable CPT, and antitumor compositions comprising solutions of lactone stable CPT. Additionally, this invention claims novel dosages, schedules of administration, and routes of administration of CPT formulations to humans with various forms of cancer.
2. Description of the Related Art
A. Introduction to DNA Topoisomerases
Several clinically important anticancer drugs kill tumor cells by affecting DNA topoisomerases. Topoisomerases are essential nuclear enzymes that function in DNA replication and tertiary structural modifications, such as overwinding, underwinding, and catenation, which normally arise during replication, transcription, and perhaps other DNA processes. Two major topoisomerases that are ubiquitous to all eukaryotic cells: (1) Topoisomerase I (topo I) which cleaves single stranded DNA; and (2) Topoisomerase II (topo II) which cleaves double stranded DNA. Topoisomerase I is involved in DNA replication; it relieves the torsional strain introduced ahead of the moving replication fork.
Topoisomerase I purified from human colon carcinoma cells or calf thymus has been shown to be inhibited by CPT. CPT, CPT-11 and an additional Topo I inhibitor, topotecan, has been in used in clinical trials to treat certain types of human cancer. For the purpose of this invention, CPT derivatives include CPT-11, 10-hydroxy 7-ethyl camptothecin (HECPT), 9-amino camptothecin, 10, 11 methylenedioxy camptothecin and topotecan. These CPT derivatives use the same mechanism to inhibit Topo I; they stabilize the covalent complex of enzyme and strand-cleaved DNA, which is an intermediate in the catalytic mechanism. These compounds have no binding affinity for either isolated DNA or topoisomerase I but do bind with measurable affinity to the enzyme-DNA complex. The stabilization of the topoisomerase I "cleavable complex" by CPT and derivatives is readily reversible.
Although CPT and the aforementioned CPT derivatives have no effect on topoisomerase II, these CPT derivatives stabilize the "cleavable complex" in a manner analogous to the way in which epipodophyllotoxin glycosides and various anthracyclines inhibit topoisomerase II.
Inhibition of topoisomerase I by CPT and derivatives induces protein-associated-DNA single-strand breaks. Virtually all of the DNA strand breaks observed in vitro cells treated with CPT are protein linked. However, an increase in unexplained protein-free breaks can be detected in L1210 cells treated with CPT. The compounds appear to produce identical DNA cleavage patterns in end-labeled linear DNA. It has not been demonstrated that CPT or CPT derivatives cleaves DNA in the absence of the topoisomerase I enzyme.
B. Activity of Camptothecin and Derivatives is Cell Cycle Specific
The activity of CPT is cell cycle specific. The greatest quantitative biochemical effect observed in cells exposed to CPT is DNA single-strand breaks that occur during the S-phase. Because the S-phase is a relatively short phase of the cell cycle, longer exposure to the drugs results in increased cell killing. Brief exposure of tumor cells to the drugs produces little or no cell killing, and quiescent cells are refractor. These results are likely due to two factors:
(1) The drugs inhibit topoisomerase I reversibly. Although they may produce potentially lethal modifications of the DNA structure during DNA replication, the breaks may be repaired after washout of the drug; and
(2) Cells treated with topo I inhibitors, such as CPT tend to stay in G0 of the cell cycle until the drug is removed and the cleaved DNA is repaired. Inhibitors of these enzymes can affect many aspects of cell metabolism including replication, transcription, recombination, and chromosomal segregation.
C. Lactone Form Stabilizes Camptothecin Antitumor Activity and Reduces Water Solubility
Utilizing HPLC and NMR techniques, researchers have demonstrated that CPT derivatives undergo an alkaline, pH-dependent hydrolysis of the E-ring lactone. The slow reaction kinetics allow one to assess whether both the lactone and non-lactone forms of the drug stabilizes the topoisomerase I-cleaved DNA complex. Studies indicate that only the closed lactone form of the drug helps stabilize the cleavable complex. This observation provides reasoning for the high degree of CPT activity observed in solid tumor models. Tumor cells, particularly hypoxic cells prevalent in solid neoplasms, have lower intracellular pH levels than normal cells. At pH levels below 7.0, the closed form of CPT predominates. Thus, the inventors maintain that CPT will be more effective at inhibiting topoisomerase I in an acidic environment than in cells having higher intracellular pH levels. It is the object of this invention to provide lactone stable CPT as the basis of the claimed subject matter. Lactone stable CPT is defined as CPT which is dissolved in DMI or DMA in the presence of a pharmaceutically acceptable acid. The presence of the acid stabilizes the lactone form of CPT. For the purpose of this invention lactone stable CPT and CPT are used interchangeably.
D. Camptothecin and Derivatives
In 1966, Wall and Wani isolated CPT from the plant, Camptotheca acuminata. In the early 1970's CPT reached Phase I and Phase II trials and was found to have antitumor activity, but it caused unpredictable myelosuppression and hemorrhagic cystitis. It is important to note that all of these studies used sodium hydroxide formulations of CPT which increased the water solubility of the molecule. Phase II studies with sodium CPT were limited because they induced unpredictable and severe myelosuppression, gastrointestinal toxicity, hemorrhagic cystitis, and alopecia. Clinical trials with sodium CPT were eventually discontinued because of unpredictable toxicities. To demonstrate the utility and novelty of the present invention it is useful to review the literature on human clinical trials conducted with sodium CPT administered parenterally.
In 1970, Gottlieb and coworkers reported on clinical studies with the sodium salt of camptothecin which were begun at the Baltimore Cancer Research Center in January 1969. In this clinical trial, CPT was administered as a rapidly running iv solution over a 5-10 minute period at a concentration of 2 mg of camptothecin sodium per milliliter of saline. Doses of CPT sodium from 0.5 to 10.0 mg/kg of actual or ideal body weight (whichever was less) were used. These investigators reported that because hemorrhagic sterile cystitis was noted in several of the early trials, patients receiving camptothecin sodium were well hydrated either i.v. or orally for 72 hours after drug administration. It is interesting to note that the mean urine recovery of CPT was 17.4% over the first 48 hours (range: 3.6-38.9%) with most of the excretion occurring in the initial 12 hours. When these investigators excluded the 5 patients with impaired excretion, the mean urine recovery of CPT was 22.8%. These investigators noted that unmetabolized camptothecin in high concentrations rapidly appeared in the urine after iv drug administration and went further to state that this finding probably accounted for the sterile hemorrhagic cystitis noted in 3 moderately dehydrated patients. Although maintaining a copious urine outflow seems able to prevent this complication, we are exploring various alterations in urine pH as another possible way of decreasing the risk of this debilitating type of toxicity.
In 1972, Muggia et. al. reported results of a Phase I clinical trial in fifteen patients treated with CPT sodium at four weekly dose levels ranging from 20-67 mg/m.sup.2. No clinical benefit was observed in eight patients with measurable disease who were treated with the 5-day courses at dose levels associated with toxicity. The drug was administered in concentrations of 1 or 10 mg/ml and it was always administered by intravenous push. Cystitis was the most prominent nonhematologic toxic effect observed in this study. Bladder toxicity was dose limiting in three patients receiving doses of 20 to 30 mg/m.sup.2, and occurred in two additional patients at doses of 44 and 30 mg/m.sup.2. Cystitis, another toxic effect occurring frequently after treatment with camptothecin, was not predicted by preclinical toxicologic studies. Our clinical experience would suggest that the occurrence of cystitis may be related to the duration of the patient's exposure to the drug. CPT is excreted unchanged by the kidneys, although a large percentage of the drug administered cannot be accounted for in the urine. It is possible that relatively less drug is excreted in the urine of animals since an extremely active transport of CPT into bile has been demonstrated. Alternatively, one needs to postulate that the mucosa of the human bladder is more susceptible to the toxic action of CPT or that the effect on the human bladder is due to some unrecognized CPT metabolite.
In 1972, Moertel and coworkers administered CPT sodium dissolved in physiologic saline at a concentration of 2 mg/ml and administered by rapid intravenous infusion over 5-10 minutes. Two schedules of administration were used in this study: (a) a single injection repeated at 3-week intervals; and (b) a 5-day course repeated ever 4 weeks. The initial dose for the single-dose method was 180 mg/m.sup.2. Because of toxic effects which were considered excessive by the investigators, later patients were treated at doses ranging between 90 and 120 mg/m.sup.2. Dosages for the 5-day course ranged between 11 and 22 mg/m.sup.2 /day (total course: 55-110 mg/m:). The toxicity and response data from this study is summarized in Table 1-Table 4. Diarrhea was only a problem at higher doses, but then could be quite severe to the point of fecal incontinence and persistent for as long as 4 weeks. Cystitis usually began about 7-10 days after treatment and was characterized clinically by dysuria and frequency. With more severe toxicity, gross hematuria developed. Pathologically, this was characterized by multiple necrotic ulcerations which could involve the entire urinary tract from kidney pelvis to bladder. According to these investigators, the occurrence of hemorrhagic cystitis did not preclude further treatment with CPT, and its severity could be titrated down by lowering the dose in subsequent courses. These investigators also reported that the more prolonged schedule produced more severe toxicity at a given total dose level, but the difference was not as great as might have been predicted by preclinical animal studies.
These investigators proposed that a reasonable initial dose of CPT sodium is 110-120 mg/m.sup.2 for the single-injection method or 17 mg/m.sup.2 /day (total dose: 85 mg/m.sup.2) for the 5-day course. They noted that after 2 months (8 or 9 weeks) only two of their 61 patients showed evidence of partial objective improvement, and none showed improvement at 3 months. Both patients who demonstrated an objective response at 2 months had large bowel cancer. These investigators concluded that CPT "is a drug of protean and unpredictable toxicity that has no clinical value in the management of gastrointestinal
TABLE 1 ______________________________________ Toxic Reactions: Single-Dose Method Nonhematologic Toxicity No. of Patients With: No. of Dose Patients (mg/m.sup.2) Treated Diarrhea Cystitis ______________________________________ 90 10 100 6 -- 2 110 2 1 1 120 7 4 2 180 9 2 3 ______________________________________
TABLE 2 ______________________________________ Toxic Reactions: 5-day Course Nonhematologic No. of Patients With: Dose No. of Patients (mg/m.sup.2 .times. 5) Treated Diarrhea Cystitis ______________________________________ 11 2 -- 1 15 9 1 4 17 5 4 2 20 10 4 6 22 1 1 -- ______________________________________
TABLE 3 ______________________________________ Relationship of Method of Administration to Cystitis Method of Administration Single Dose 5-Day Course Cystitis (% of 34 Patients) (% of 27 Patients) ______________________________________ 24 48 (P &lt; 0.05) ______________________________________
TABLE 4 ______________________________________ Objective Results ______________________________________ Single-Dose Method (34 Patients) Time after start of therapy Objective Results* 3 wks 6 wks 9 wks 12 wks ______________________________________ Improved 4 2 2 -- Stable 17 11 8 6 Worse 13 21 24 28 ______________________________________ 5-Day Course (27 Patients) Time after start of therapy Objective results* 4 wks 8 wks 12 wks ______________________________________ Improved 1 -- -- Stable 12 7 6 Worse 14 20 21 ______________________________________ *3 patients showed 25%-50% response at 3 wks only.
Gottlieb and Luce reported the results of treatment of patients with malignant melanoma with CPT sodium (1972). Fifteen patients with advanced malignant melanoma were treated with CPT at doses of 90-360 mg/m.sup.2 repeated every 2 weeks. CPT sodium was administered as a single rapid intravenous (iv) injection starting at a dose of 120 mg/m.sup.2 repeated at 2-week intervals. The dose in subsequent courses was increased by increments of 60 mg/m.sup.2 per dose (to a maximum of 360 mg/m.sup.2) in eight patients who tolerated their initial doses with minimal toxicity. To prevent the known bladder toxicity of this drug, patients were well hydrated for 3 days after therapy. None of the patients had a 50% or greater decrease in tumor diameter. Less pronounced transient tumor regression was noted in three patients, but no clinical benefit was associated with these responses. The remaining patients had no change or progression in their disease. Toxic effects included myelosuppression (11 patients), nausea and vomiting, alopecia, diarrhea, and hemorrhagic cystitis. These investigators concluded that CPT, at least as administered in this study, had little to offer the patient with advanced disseminated melanoma.
In 1972, Creaven and co-investigators reported studies of plasma CPT levels during a 5-day course of treatment. These investigators state that the toxicity of CPT has been widely and unpredictably variable in the course of initial clinical evaluation. Severe toxic effects occurred even though patients with obvious renal disease were excluded. In this study they investigated plasma CPT levels 24 hours after the administration of sodium CPT administered on a once daily .times.5 schedule to determine whether such measurements would be of value in predicting toxicity, and observed that plasma CPT levels have little relation to the dose given when the dose is in the range of 6.5-20 mg/m.sup.2 /day.
In another clinical study Muggia and co-workers reported the results of a phase I trial of weekly and daily treatment with CPT. Fifteen patients were treated at four weekly dose levels ranging from 20 to 67 mg/m.sup.2 of sodium CPT. Reversible leukopenia was the major dose-limiting toxic effect. Five-day loading courses were begun at total doses of 1.5 mg/m.sup.2 per course because increased sensitivity to daily administration had been noted in animal studies. Leukopenia was more prolonged after daily treatment than after weekly treatment and occurred in four of six patients receiving a total dose of 100 mg/m.sup.2. Tolerance to 5-day courses was an unexpected result. Also unpredicted by preclinical studies was man's susceptibility to cystitis with either schedule of treatment. They noted clinical responses in two of ten patients in whom response could be evaluated after weekly courses of treatment. No clinical benefit was observed in eight patients with measurable disease who were treated with the 5-day courses at dose levels associated with toxicity. Cystitis was another toxic effect occurring frequently after treatment with CPT, was not predicted by preclinical toxicologic studies. The investigators suggested that the occurrence of cystitis may be related to the duration of the patient's exposure to the drug, and proposed that CPT is excreted unchanged by the kidneys, although a large percentage of the drug administered cannot be accounted for in the urine. They also proposed from this study that it is possible that relatively less drug is excreted in the urine of animals since an extremely active transport of camptothecin into bile has been demonstrated. They also postulated that the mucosa of the human bladder is more susceptible to the toxic action of camptothecin or that the effect on the human bladder is due to some unrecognized CPT metabolite.
There are several features which are common in these studies with sodium CPT. First is the use of sodium CPT which made the CPT more water soluble. The hydrolysis of lactone E ring to form the carboxylate species by formulating CPT in sodium hydroxide. The antitumor activity of the carboxylate form of CPT is reduced by at least 10-fold, which partially accounts for the lack of clinical response in these studies. Second is the rapid intravenous administration of the drug. CPT is an S-phase specific drug and therefore will exert a greater antitumor effect under conditions of prolonged exposure, as in a continuous intravenous infusion. The short infusion (i.v. push or rapid i.v. infusion) times in all of these studies do not allow a long enough exposure time to the drug at suitable levels, and is further compounded by the administration of the water soluble carboxylate form of CPT. A third common feature is the notable frequency of cystitis in these studies using sodium CPT.
The novel features of the present invention include the following: (1) pharmaceutically acceptable formulations which allow the direct parenteral administration of lactone stable CPT to human subjects with cancer, (2) pharmaceutically acceptable formulations which allow the direct oral administration of lactone stable CPT to human subjects with cancer, and (3) dosages and schedules for the administration of lactone stable CPT to patients with cancer by parenteral and oral routes of administration. The methods of use for the instant invention will allow the physician to titrate the dose of lactone stable CPT which is predicted to significantly reduce the frequency of hemorrhagic cystitis relative to the administration of sodium CPT. The inventors predict that by administering the carboxylate species of CPT a higher incidence of renal toxicity is observed than would be observed if the lactone species of CPT were administered.
Inventors claim that reason previous use of sodium CPT caused hemorrhagic cystitis relates to the enhanced renal excretion of the carboxylate form of CPT which when exposed to the lower pH (.about.pH 5) of the distal convoluted tubule in the kidney, the carboxylate form of CPT is converted to the lactone form of CPT. The formation of the lactone form in high concentration at the distal convoluted tubule resulted in a high concentration of the lactone form of CPT being excreted into the collecting duct and into the ureters and bladder which resulted in hemorrhagic cystitis. Elimination of CPT by the renal route is enhanced by administration of the carboxylate form and is reduced by administration of the lactone form. Inventors believe that by administering CPT orally or parenterally to patients substantially in the lactone form that renal elimination of CPT will be minimal and further that the incidence of hemorrhagic cystitis will be significantly reduced in patients who receive the formulations of CPT claimed in this invention.
In addition to the previously noted toxicities and limited clinical responses to CPT, CPT has also been considered unsuitable for direct clinical use because it is poorly soluble in water. One useful purpose of this invention is to formulate CPT in a pharmaceutically acceptable manner using an organic solvent or a mixture of organic co-solvents to stabilize CPT in the lactone ring form. It is this lactone stable CPT which permits direct administration of CPT to cancer patients. An additional purpose of this invention to provide certain indications, schedules, dosages and routes of administration of lactone stable CPT for the purpose of treating cancer in humans.
The selection of suitable organic solvents for pharmaceutical dosage forms is limited to those which have a high degree of physiological safety. This invention describes administration of lactone stable CPT in a pharmaceutically acceptable multi-solvent formulation, overcomes interpatient variability and drug resistance as it relates to the prodrug CPT-11 conversion to HECPT and is useful in instances where human cancer cells, because of their altered enzymatic activity, resist metabolic conversion of CPT-11 to HECPT.
Two CPT derivatives, CPT-11 and topotecan, have less sporadic toxicities but retain significant activity of the parent compound. CPT-11 and Topotecan are currently undergoing Phase I and Phase II development in the United States. 10,11 methylene dioxycamptothecin is reportedly very active in preclinical studies, but it is also reported to be relatively insoluble in water which limits its use in the clinic (Pommier, et al. 1992).
Kunimoto and co-workers demonstrated in preclinical studies of CPT administered at similar dosages of 10-100 mg/kg intraperitoneally to CDF1 mice implanted with intraperitoneal LD1210 leukemia demonstrated superior T/C (treated/control) ratios relative to mice treated in the same manner with 7-ethyl camptothecin (ECPT) and 10-hydroxy 7-ethyl camptothecin (HECPT). Their results with CPT, ECPT and HECPT were inferior to that of CPT-11 administration under the same conditions. The inventors of the current invention believe that the lesser activity observed by Kunimoto is related to the lack of an optimized pharmacologic schedule for CPT. The instant invention takes into account the requirement for administration of the lactone stable species of CPT by a prolonged, not bolus, parenteral infusion or by the repeated oral, parenteral or topical administration of the drug in a manner which closely replicates the pharmacokinetics of a continuous parenteral infusion.
Tables 5 and 6 present data summarizing Phase I and Phase II clinical trials of CPT-11. Neutropenia and diarrhea are the major reported, dose-limiting toxicities of CPT-11.
TABLE 5 __________________________________________________________________________ PHASE I STUDIES CPT-11 Investigator Schedule # Pts Dose Toxicity Tumor Type __________________________________________________________________________ Clavel et al 90 min. 37 115 mg/m.sup.2 /d Neutropenia* Breast (1 PR) QDx 3 Q21 days (33-115) diarrhea, Mesothelioma nausea and (1 PR) vomiting, alopecia Culine et al 90 min. 59 150 mg/m.sup.2 /wk Neutropenia* esophagus Q21 days (50-150) diarrhea* (1 PR) cervix vomiting, (1 PR) renal alopecia (1 PR) ovarian fatigue (1 PR) stomatitis Neutropenia* Negoro et al 30 min 17 100 mg/m.sup.2 Diarrhea*, N/V, NS CLC (2 PRs) infusion (50-150) alopecia, weekly liver dysfunction Ohe et al 120 hr CI 36 40 mg/m.sup.2 /d Diarrhea* None Q3 wks (5-40) nausea and vomiting, thrombocytopenia, anemia, liver dysfunction Diarrhea* Rothenberg et al 90 mg QWx 4 32 180 mg/m.sup.2 /wk Neutropenia, Colon Ca (2 PRs) Q42 days (50-180) nausea, vomiting, alopecia Rowinsky et al 90 min 32 240 mg/m.sup.2 Neutropenia* Colon Cancer (1 PR) infusion (100-345) vomiting, Cervix Ca Q21 day diarrhea abd. (1 PR) pain, flushing __________________________________________________________________________ *Dose Limiting Toxicity
TABLE 6 __________________________________________________________________________ CPT-11 PHASE II TRIALS Investigator Tumor Type Schedule # Pts. Response Rate Reported Toxicities __________________________________________________________________________ Fukuoka et al Untreated 100 mg/m.sup.2 weekday 73 (23/72) PRs Neutropenia, Non Small 31.9% diarrhea, Cell Lung nausea, Cancer vomiting, anorexia, alopecia Masuda et al Refractory or 100 mg/m.sup.2 weekly 16 (7/15) PRs Neutropenia, Relapsed 47% diarrhea Small Cell pneumonitis Lung Cancer (12.5) Negoro et al Small Cell 100 mg/m.sup.2 /weekly 41 2 CRs Neutropenia (38.6%) Lung Cancer and N/V (61.5%) 7 PRs diarrhea (53.8%) 33.3% alopecia (40.0%) Ohno et al Leukemia/ 200 mg Q3 No resp. 62 ** Neutropenia (91%) Lymphoma 40 mg/m.sup.2 Q0x5 Thrombocytopenia 34% PR Gastrointestinal 20 mg/m.sup.2 bid x7 (76%) 25% RR Shimada et al Colon cancer 100 mg/m.sup.2 /week 17 6/17 (PR) Neutropenia (53%) or 46% N/V (35%) 150 mg/m.sup.2 /Q 2 wks diarrhea (24%) Takeuchi et al Cervical 100 mg/m.sup.2 weekly 69 SCR Neutropenia (89%) Cancer 150 mg/m.sup.2 weeks 8 PR N/V (51%) RR of Diarrhea (39.1%) 23.6% Alopecia (38.1%) __________________________________________________________________________ **see text
E. HECPT is the Active Metabolite of CPT-11
Preclinical data, obtained by Barilero et al. on animals and more recently on humans, suggest that HECPT is the active metabolite of CPT-11 in vivo. Several different researchers administered CPT-11 and HECPT intravenously during Phase I trials and recorded the peak plasma concentrations (CpMax) at the end of the infusions. An analysis of the published mean peak plasma concentrations indicates that approximately 1.5% to 9% of the administered CPT-11 (on a per/mg basis) is converted into HECPT. The pharmacokinetic data from 30-minute intravenous infusions show a lower percentage of conversion (.about.1.5%) of CPT-11 to HECPT than that observed following more prolonged infusions (.about.9% at 40 mg/m.sup.2 /d.times.5). The reported half life of HECPT observed in humans following the administration of CPT-11 ranges from 8.8 to 39.0 hours.
The biochemical and pharmacological relationship between CPT-11 and HECPT, as well as the role these compounds play in killing cancer cells in vivo is not completely understood. Investigators studying in vitro tumor cell lines have reported that HECPT has a 3600-fold greater inhibitory activity than CPT-11 against topoisomerase I in P388 cells and that HECPT is approximately 1000-fold more potent in generating single-strand DNA breaks in MOLT3 cells (Kawato, et al (1991)). However, Kaneda et al. report that HECPT has little anti-tumor activity compared to CPT-11 in vivo. They base their findings on studies conducted using an intermittent bolus schedule (days 1, 5, and 9) and an i.p. route of administration with an intraperitoneal P388 tumor model in mice.
Ohe et al. suggest that HECPT is a more toxic moiety of CPT-11 and could be responsible for much of the toxicity attributed to CPT-11. However, these same investigators noted a lack of correlation between HECPT pharmacokinetics and dose or CPT-11 pharmacokinetics and toxicity in human subjects. Furthermore, Ohe et al. noted a large range of interpatient variability in the AUC of CPT-11 and its metabolism to HECPT, which may result in unpredictable variability in the pharmacokinetic behavior, clinical anti-tumor effects, and toxicity in the individual patient. The data Ohe et al. obtained (using a 5-day, continuous intravenous infusion of CPT-11) also suggests that the conversion of CPT-11 to HECPT is a saturable process. If this is so, the clinical approach to maximizing dose intensity of the active metabolite would impose additional limitations on the effective use of CPT-11.
In preclinical studies of xenografts of human tumors in nude mice, Kawato et al. report that the sensitivity of human tumors to CPT-11 is independent of their ability to produce HECPT and that the effectiveness of CPT-11 is not related to the ability of the tumor to produce HECPT. Kawato et al. suggests that HECPT production is likely to be mediated in the plasma or interstitial compartment. Kaneda et al. observed that the plasma concentration of HECPT in mice was maintained longer after CPT-11 administration than after treatment with HECPT and suggested that clinicians should maintain plasma levels of HECPT to enhance the antitumor activity. of CPT-11. The present invention has a useful advantage of not requiring activation by an enzyme in order to form the active species (as with CPT-11) and the additional advantage of being able to directly control the interpatient variability.
One of the advantages of present invention provides clinicians with the ability to directly adjust the plasma levels of CPT to the point of therapeutic tolerance by controlling the dose and the schedule of administration. The inventors contend that this should lead to a superior ability to achieve better antitumor activity and reduce interpatient variability of the plasma levels of CPT.
The different observations made in these studies suggest that direct administration of CPT by parenteral and oral administration could provide significant clinical benefit for the treatment of cancer. However, in the past, CPT has been considered insufficiently water soluble and too toxic for clinical use. The current invention overcomes the solubility problem by providing lactone stable pharmaceutically acceptable multisolvent formulations of CPT for parenteral use and also oral CPT formulations.